Skepticism

EVENTS

The genesis of schizophrenia

Lately, my genetics class has taken a turn, by intent. I start the semester with the basics: Mendel, simple crosses, learning the terminology, all of that simple stuff that most of them see as a review of high school biology. But then, once I’m reasonably confident they know the commonly understood rules, I start adding all the complications that Mendel knew nothing about, and then we start getting into epistasis and the complicated business of translating genotype into phenotype, and I essentially end up telling them that everything they learned before wasn’t exactly true, because real world heredity is a heck of a lot more complicated. You can’t usually reduce complex traits to one gene with alleles that are dominant or recessive.

So what do you know, the New Yorker comes out with an excellent article that highlights complexity and real world genetics: Runs in the Family, about the genetics of schizophrenia.

The notion that a mental illness could be carried across generations by unitary, indivisible factors—corpuscles of information threading through families—would have struck most of Bleuler’s contemporaries as mad in its own right. Still, Bleuler was astonishingly prescient about the complex nature of inheritance. “If one is looking for ‘the heredity,’ one can nearly always find it,” he wrote. “We will not be able to do anything about it even later on, unless the single factor of heredity can be broken down into many hereditary factors along specific lines.”

In the nineteen-sixties, Bleuler’s hunch was confirmed by twin studies. Psychiatrists determined that if an identical twin was schizophrenic the other twin had a forty-to-fifty-per-cent chance of developing the disease—fiftyfold higher than the risk in the general population. By the early two-thousands, large population studies had revealed a strong genetic link between schizophrenia and bipolar disorder. Some of the families described in these studies had a crisscrossing history that was achingly similar to my own: one sibling affected with schizophrenia, another with bipolar disorder, and a nephew or niece also schizophrenic.

“The twin studies clarified two important features of schizophrenia and bipolar disorder,” Jeffrey Lieberman, a Columbia University psychiatrist who has studied schizophrenia for thirty years, told me. “First, it was clear that there wasn’t a single gene, but dozens of genes involved in causing schizophrenia—each perhaps exerting a small effect. And, second, even if you inherited the entire set of risk genes, as identical twins do, you still might not develop the disease. Obviously, there were other triggers or instigators involved in releasing the illness.” But while these studies established that schizophrenia had a genetic basis, they revealed nothing about the nature of the genes involved. “For doctors, patients, and families in the schizophrenia community, genetics became the ultimate mystery,” Lieberman said. “If we knew the identity of the genes, we would find the causes, and if we found the causes we could find medicines.”

Read the whole thing, it’s very good. It also talks about a glimmering of understanding that is gradually emerging — that there is a correlation with certain alleles in proteins of the immune system, which sounds weird until you find the connection, that these same proteins are involved in synaptic remodeling by microglia, and it all begins to make sense. But it’s still not simple.

Comments

A good science/detective story. The results seem to tie a lot of observations together.
There doesn’t appear to be a cure once the synapses have been pruned. If there was method, that if applied at the right time, that would suppress the excessive pruning, it might prove to be beneficial.

even if you inherited the entire set of risk genes, as identical twins do, you still might not develop the disease

The next question is, if the risk genes aren’t present at all, can you still develop “schizophrenia”? Or should there be different terms for the set of behaviors, from the genetic predisposition? The same questions will apply to ASD.

What I love about the twin studies and heritability studies is that they show that there is some kind of underlying cause/effect relationship that is not purely behavioral. So it’s right to call it a “disease” instead of (what? maybe:) a disorder. I’ve always been worried that psychology was going out on a limb when they started classifying diseases by behavioral outcomes – admittedly, there isn’t anything else to do, but if you look at the DSM for something like “narcissistic personality disorder” it’s very hard to see that as anything other than a clustering category of behaviors, which is very different from something like schizophrenia which appears to involve an actual physical precursor condition.

That’s a wonderful article; I love the graceful portrait of the author and his father that starts it off. Mukerjee is also the author of “Cancer: the emperor of maladies” – which I highly recommend.

I still wonder if we’ll discover that there’s some environmental factor, like mercury or automotive lead or some virus and humanity will have a great big forehead-slapping session. On one hand it would be great to discover such a thing, because we could collectively avoid it, but on the other it would mean so much pointless suffering.

Over the past couple of years I have been involved in studying the biological mechanisms of psychiatric disorders (my main focus is on autism and a bit of schizophrenia).
We know very little about the “causes” of schizophrenia or many other complex mental illnesses. The reason for that is obvious; brain is very complex. Many genes have been identified for autism and schizophrenia and as Jeff Lieberman said, they might each contribute a little to the total risk (keep in mind that many genes that are found in one study are not replicated in others). The huge amount of interactions between these genes as well as between genes and environment and the effect of environment itself is really difficult to study and need enormous statistical power. Add to this list the more basic concepts of genetics like heterogeneity, pleiotropy, mosaicism,… and you will get an enormous challenge.

As for the effect of environment, one of the most famous studies showed a significant effect of Dutch famine on incidence of schizophrenia (http://link.springer.com/article/10.1007/s001270050068). Since then, people have studied many environmental factors (birth complications, infections during pregnancy, maternal smoking, etc.) , but we are far from done here.

As for the inflammation, that is a well-know fact that nearly all major psychiatric disorders are associated with changes in the immune system. Even anti-inflammatory ( and immunomodulatory) drugs have been used (with variable success rate) to help alleviate the symptoms of depression, schizophrenia, bipolar disorder, etc. There are polymorphisms on immune-system related genes that are associated with mental disorders like depression. It has been suggested that this might have an evolutionary purpose (see this http://www.ncbi.nlm.nih.gov/pubmed/26711676 for a good review)

NIMH has introduced this so-called Research Domain Criteria that now looks at domains rather than just disorders. This *might increase our understanding of mental illness (and consequently its causes), because it allows us to study symptoms as a continuous rather than black/white phenomena.

The next question is, if the risk genes aren’t present at all, can you still develop “schizophrenia”?

Yes, drug induced psychosis and mood disorders are a real side effect of several different chemicals. I seem to remember that LSD and Mescaline have long been studied because they alter perception in the same way that people with schizophrenia experience hallucinations.

Since people often carry the same genes without developing any mental illness, and the same mental state can be chemically induced; it seems clear that like any human behavior, it is almost impossible to separate nature from nurture.

The difficulty with mental illnesses is that schizophrenia is that it is not just one disease. It is probably many different diseases, so it may manifest with more bipolar symptoms. Sometimes it is difficult to diagnose with complete accuracy. So someone with bipolar may be diagnosed with schizophrenia

There have been studies showing more winter births among people with schizophrenia. I think this has been replicated in tropical countries in that there are more rainy season births among people with schizophrenia

“Psychiatrists determined that if an identical twin was schizophrenic the other twin had a forty-to-fifty-per-cent chance of developing the disease—fiftyfold higher than the risk in the general population.”

The appropriate comparison group for an identical twin study is non-identical twins. Otherwise you fail to control for family-dependent environmental factors. A few minor quibbles with the article, but overall well done.

I seem to remember that LSD and Mescaline have long been studied because they alter perception in the same way that people with schizophrenia experience hallucinations.- Tethys@6

Not really: the phenomenology is quite different. The claimed similarity was a part of anti-drug propaganda. That said, if you suspect you might be prone to schizophrenia, you’d be well-advised to steer clear of psychedelics, and cannabis, as both can provoke paranoia.

Number one, – anybody who is classified as being nothing but a typical Jack-of-all-trades kind of person, via having being born with a wise brain which learns laterally and slowly, can independently discover by his or herself, that which is today known as Albert Einstein’s theory of special relativity.

Number two, – anybody who was born with a very stupid gullible brain, thus born with a brain that accepts incoming data without questioning it, will quickly move to the top of the class in grade school, whip through university, and pop out the other end with multiple PhD’s.

A person with the Jack of all trades personality can extend his or her mind laterally at the ground based foundation level. If extending laterally far enough, this person can eventually understand the basics of the entirety of reality, at that foundation level. But despite this achievement, this person will be totally ignored due to having nothing but a so called Jack of all trades personality.

However, those who have PhD’s, and thus are confined to being experts in only specific fields, will be listened to. Despite possessing vast amounts of knowledge, mixed with a dash of intelligence, these people are regarded in general as being the intelligent people that are to be listened to.

As a consequence, schizophrenia is still misunderstood, all thanks to those whose minds are imprisoned within mere fields of expertise, such as the imprisonment of the field of psychiatry. This misunderstanding is then endlessly preached across the globe.

Most psychiatrists experience, on an ongoing daily basis, O.C.C.D.
This is an Obsessive Compulsive Certainty Disorder.

As stated, in general, psychiatrists are absolutely certain that schizophrenia is a mental disorder, a mental illness. Yet they also say that they do not fully understand schizophrenia, and as a result of this you constantly hear about new ideas concerning its structure and cause.

To be absolutely certain that schizophrenia is a mental illness, ones mind must encompass it completely, thus absolutely. Yet again, psychiatrists admit that they have not fully encompassed schizophrenia, and thus research concerning its structure and cause, continues to go on and on.

Thus in this case it is to be noted that psychiatrists are absolutely certain that they can fully encompass something that they can not fully encompass, hence they constantly are showing the symptoms of O.C.C.D.